Atrial fibrillation (AF) is the commonest cardiac arrhythmia and in its chronic form affects more than two million patients in the USA. AF is associated with cardiac and non-cardiac diseases. About 10% of cases have no obvious cause (lone AF). Stroke is the commonest complication with a 25% greater risk than control in older age groups. Drugs that block sodium, potassium and calcium channels provide the customary treatment. All of these drugs may have toxic side effects because their ion cannel targets are present in ventricle where block may produce lethal arrhythmias. Our long-term objective is to develop a satisfactory drug for AF. As a first step we have identified a novel target that is limited to human atrium and should therefore be free from the risk of ventricular arrhythmias. The specific aim of this proposal is to discover novel, selective drugs acting on this atrial-delimited target for the treatment of AF. The novel target will be expressed in cell lines for use in high throughput functional screens of small compounds derived from directed and diversity libraries. Confirmed leads will be fully characterized and two to five preclinical drug candidates should be available within two years. PROPOSED COMMERCIAL APPLICATIONS: Atrial fibrillation is a very common disease for which there is no satisfactory treatment. A drug that has high efficacy with little toxicity would have great therapeutic and commercial value.